N, n-alkylene-imino-lower alkanoamidine compounds



United States Patent 0 3,189,601 N,N-ALKYLENE-IMJNG-LGWER ALKANO- AMIDINE COMPUUNDS Robert Paul Mull, Florham Park, N.J., assignor to Ciha Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Jan. 10, 1954, Ser. No. 336,881

laims. or. 260-439 (or l-pyrrolidino), N,N-pentamethyleneirnino (or lpiperidino), N,N-hexamethyleneimino (or l-hexahydroazepino), N,N-heptamethyleneimino (or l-octahydroazocino), N,N-octamethyleneimino (or l-octahydroazonino), N,N-nonamethyleneimino (or l-decahydroazecino), N,N- decamethyleneimino and the like.

The carbon atoms of an N,N-alkylene-irnino, an N,N- (N R aza alkylene)-imino, an N,N-bicycloalkyleneimino, or an N,N-(N-R -aza-bicycloalkylene)-imino radical may be substituted by aliphatic radicals, such as lower alkyl, particularly methyl, as well as ethyl, n-propyl, isopropyl and the like.

The lower alkylene radical, linking R with the amidino group, is represented by lower alkylene having from one to seven carbon atoms. Preferably, lower alkylene has from two to three carbon atoms, which separate the group R from the amidino group by the same number of carbon atoms; such radicals are 1,2-ethylene, l-methyl- 1,2-ethylene, 2-methyl-l,2-ethylene or 1,3-propylene. Other lower alkylene radicals are, for example, methylene, 1,1-ethylene, 2,3-butylene, 1,3-butylene, 1,4-butylene, 1,4-penty1ene, 1,5-pentylene and the like.

The amidino group may be represented by the formula in which each of the radicals R R and R stands primarily for hydrogen. They may also represent organic radicals, such as aliphatic radicals, particularly lower alkyl, e.g., methyl, ethyl, n-propyl, isopropyl and the like. Each of the radicals R and R may also be the acyl radical of an organic carboxylic acid; such acyl radical represents, for example, the acyl radical of a lower aliphatic carboxylic acid, for example, a lower alkanoic acid, e.g., acetic, propionic, pivalic acidand the like, a substituted lower alkanoic acid, e.g., chloroacetic, dichloroacetic, hydroxyacetic, methoxyacetic, 3-cyclopentylpropionic acid and the like, or a lower alkenoic acid, e.g., 3- butenoic acid and the like, a carbocyclic aryl carboxylic acid, for example, a monocyclic carbocyclic aryl carboxylic acid, e.g., benzoic, Z-hydroxy-ben'zoic, 4-methoxybenzoic, 3,4-dimethoxy-benzoic, 3,4,5-trimethoxy-benzoic, 4-0-ethoxycarbonyl-syringic, 3,4-dichlorobenzoic, 3-N,N- dimethyl-amino-benzoic, 4-nitrobenzoic acid and the like, or a bicyclic carbocyclic aryl carboxylic acid, e.g., lnaphthoic, Z-naphthoic acid and the like, or a heterocyclic aryl carboxylic acid, for example, a monocyclic heterocyclic aryl carboxylic acid, e.g., nicotinic, isonicotinic, 2-furoic acid and the like.

3,189,601 Patented June 15, 19 65 ice Salts of the new compounds of this invention are particularly pharmacologically and therapeutically acceptable, non-toxic acid addition salts, such as those with inorganic acids, for example, mineral acids, e.g., hydrochloric, hydrobrorm'c, sulfuric, phosphoric acids and the like, or those with organic acids, such as organic carboxylic acids, e.g., acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, ascorbic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnarnic, mandelic, salicyclic, 4-aminosalicyclic, 2-phenoxybenzoic, Z-acetoxybenzoic acid and the like, or organic sulfonic acids, e.g., methane sulfonic, ethane sulfonic, Z-hydroxyethane sulfonic, p-toluene sulfonic acid and the like. Monoor poly-salts may be formed.

The new compounds of this invention and the salts thereof cause in the anesthetized, normotensive dog an inhibition of the carotid occlusion reflex pressor responses and antagonize pressor responses elicited by high doses of pressure substances, such as amphetamine, and lower the arterial pressure in the unanesthetized renal or neurogenic hypertensive dog. These effects appear to be due to an inhibition of the release and/ or distribution of transmitter substances from sympathetic nerve terminals. In view of these efiects, the compounds of this invention can be used as antihypertensive agents to relieve hypertensive conditions, particularly those of neurogenic, renal or essential nature. In additionycompounds of this invention cause an increaset in peripheral blood flow and can, therefore, be used in functional peripheral vascular disesases, such as Raynauds disease.

A preferred group of compounds of this invention may be represented by the compounds of the formula in which R has the previously-given meaning, i.e., represents hydrogen or methyl, It stands for one of the numbers 5, 6, 7 or 8, and A represents lower alkylene, which has preferably. from two to three carbon atoms, and separates the amidino group from the n,n-alkylene-imino group by from two to three carbon atoms, or pharmacologically acceptable acid addition salts thereof, particularly those with suitable inorganic mineral acids. Specific members of this group are, for example, 2-(1- piperidino -propionamidine, 3-( l-piperidino -butyroamidine, 2 (l-N,N-hexamethylene-imino) propionamidine, 3 (1-N,N-hexamethylene-imino) -butyroamidine, 2-[1- N,N (3-methyl-hexamethylene),-imino]-propionamidine, 2 l-N,N-heptamethylene-imino)-propionamidine, 2-[1- N,N-(4-methyl-heptamethylene)-imino] mpionamidine, 3 (1-N,N-heptamethylene-imino) butyroamidine, 2-(1- N,N-octamethylene-imino)-propionamidine and the like, and pharmacologically acceptable acid addition salts thereof, particularly with suitable mineral acid.

The compounds of this invention may be used in the form of pharmaceutical preparations, which contain the new compounds in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there may be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol, polyalkylene glycols or any other known carrier for medicaments. The pharmaceutical preparations may be in the solid form, for example, as capsules, tablets, dragees and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If

tor example, 7 a salt, "e.g., hydrochloride, and the like, of a hydroxylamine, preferably in the presence. ota suitable base,

desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, .bur'ters, etc.

7 They may also contain, incombination, other pharmacologically useful substances. 7

The compounds of this invention 'may be. prepared according to known methods. Generally, they are manufactured by converting 'in an R-lower alkano-nitrile or in a reactive, functionally converted derivative of such R- lower alkano-nitrile, in which R has the previously-given meaning, or a salt thereof, the nitrile group orfthe reactive, functionally converted nitrile group, respectively, into an amidino group, and, if desired, replacing in a resulting compound a hydrogen attached to a nitrogen atom of the amidino group by an aliphatic radical, and/ or, if desired, convertinga resulting salt into thefree base, and/ or, if desired, converting a resulting compound into a salt or into an acyl derivativerthereof.

. Reactive, functionally convertedderivatives of the R- lower 'alkano-nitriles are represented, for example, by R- to be included within the scope of this invention, Partic- I ularly useful are the compounds of the formulae GLT I J and lower alkano-amidoximesylower'alkyl R-lower alkanoimidates or lower alkyl R-lower alkano-thioimidates,- R-

lower alkanethiocarboxylic acid amides, in which R has the previously-given meaning, or any other analogous compound derived froma nitrile. Conversion of the nitriles or the reactive, functionally converted derivatives thereof into the desired ,amidines. is carried out according toknown methods, which depend largely on the nature of a the group to be converted.

, Thus, the compounds of this inventionmay be prepared by' treating an R-lower alkano-amidoxime, in which R has the previously-given rneaning, or-a salt thereof,

in which R represents hydrogen or methyl, R stands for lower alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, n butyl and the like, It stands for one of the numbers 5,6, 7 8, and A,'representing lower alkylenewith from two to three carbon atoms, separates the lower: alkyl imidate and the'lower alkyl thioimidate grouping, respectively, from the l LN-alkylene-imino group by from two to three carbon atoms, or acid addition, particularlymineral acid addition, salts thereof;

The compoundsof this invention may alsobeprepared V by reacting an R-lower alkane thiocarboxylic acid amide 'with' a, reducing reagent, and, if desired, carrying out the optional steps.

The above procedure is drogen using'a metal catalyst: containing a metal of the preferably carried out by treat-' ing the starting material with catalytically' activated hyeighth group of the peiodic's'ystem, for example, rhodium and the like. the preferred catalyst: Treatment with hydrogen may be carried out under atmospheric pressure or under increased pressure, at room temperature or at an elevated temperature, preferably ,while shaking.

. The starting materials used 'n the above: procedure are known or may be prepared according to'known methods, by reacting an R-lower alkano-nitrile with such as an alkali metal lower alkanolate, e.g., potassium methanola te', sodium ethanolate and the like.

The compounds of this invention may also be obtained by reacting a lower alkyl R-lower alkano-imidate or a lower alkyl R-lower alkano-thioiniidate, in whiclrR has the previously-given meaning, .,or a salt thereof, with. ammonia or an amine or a salt *of such reagents, and, if

desired, carrying out the optional steps. V V a Treatment with ammonia or an amine or a salt of such reagents is carried out according to known methods; liquid ammonia or, more preferably, aqueous ammonia or ammonia in an inert organic solvent, such a lower alkanol, e.g., methanol, ethanol and the like, may be used.

,Thereaction takes place'while cooling, atroorn temperature or at an elevated temperature, it necessary, in a, closed vessel and/or in the atmosphere of nitrogen;

The starting materials used in'the above procedure may be prepared according to known methods, for example,

by treating an R-lower alkano-nitrile Witha lower alkanol,

e.g., methanol, ethanol and the like, or a lower alkylmercaptan, e.g., methylmercaptan, ethylmercaptan and The above starting'materials, i.e., the lower alkyl R- thioimidates, or salts thereof, are new and are intended Rhodium on aluminum oxide represents any other suitable diluent.

with ammonia or an amine,

heoptional steps.

The above reaction is carried out according to'known methods, for example, bytreating thefstarting material with concentrated aogaeous ammonia, preferably in the presence of a reagent capable of forming insoluble sulfides, e.g'. mercuric chlc-ride. The starting materials are prepared according to known methods.

Thecompounds of this invention may also be menu-f factured from thenitriles themselves, toreigamplmby; reacting an l t-lower alkano-nitrilewith a metal amide, and, if desired, carrying out the optionalsteps. 7

The above treatment of the nitrile starting'material with a metal amide, such as an alkalismetal amide,'.e.g. -sodium amide, potassium amide and the like, or an alkaline earth metalamide, e.g.,.calcium amide and the like,'is carried out in an inert, anhydrous medium, e.g., benzen toluene, xylene; anisole and the like, or, in liquid ammonia, or A resultingfmetal salt'of the desired amidine is converted into the free compound'by hydrolysis with water'at alow temperature or'with an anhydrous solution of an acid,e.g., hydrogen chloride and the like, for example,'ina lower alkanol, e.g.,ethanol and the like; the latter treatment afiords the formation of an acid addition salt. The nitriles 'used as the starting ma-- terials are known or may be prepared according to the methods used to manufacture the known ones. a

The nitriles may also be converted into amidinesof this invention by treating an R-lower'alkano-nitrile with ammonium chloride, and, if desired, carrying out the optional steps;

The above-described treatment with ammonium chloride is preferablycarried out in the presence of liquid ammonia, if'necessary, in a closed vessel.

A hydrogen attached to one of the nitrogen atoms of the amidino group in resulting compounds maybe relaced by an organic, such as an aliphatic, radical, {par- 'ticularly by lower alkyl, according to'known methods, for

example, by treatment with a reactive ester. of an alcohol, such as an aliphaticalcohol, particularly a lower alkanol. Such esters are primarily those formed by the alcohols,

such as the lower alkanols', with strong inorganic acids,

. i the like,'in the presence of an acid, preferablyla gaseous 'acid, e.g., hydrogen chloride and the like.

'lower alkano-imidates and lower alkyl R-lower alkanoe.g., hydrochloric, hydrobromic, hydri-odic, sulfuric acid 1 and the like, or strong organic sulfonicacids, e.g.,p-toluene sulfonic acid and the like, and are represented primarily by aliphatic halides, particularly lower alkyl halides,

' e.g., methyl, ethyl, npropyl,isopropyl chloride, bromide or iodide and the like, di-lower alkyl sulfates, e.gl, dimethyl sulfate, diethylsulfate and the like, or any other. suitably. esterified aliphatic alcohol. Treatment of the amidine compound with the reactive ester compound is preferably and, if desired, carrying out carried out at an elevated temperature, it necessary, in a closed vessel under pressure.

Depending on the conditions used, the compounds of this invention are obtained in the form of the free bases or the salts thereof. A salt may be converted into the free base, for example, by reacting it with an alkaline reagent, for example, with an alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, or any other suitable reagent, particularly an anion (hydroxyl) exchange resin. A free base may be converted into its therapeutically useful acid addition salts by reaction with one of the inorganic or organic acids described hereinbefore, for example, by treating a solution of the base in an inert solvent or solvent mixture with the acid or a solution thereof.

Acylation of the resulting amidine compounds may be carried out, for example, by treatment with the reactive derivative of a carboxylic acid, for example, with the halide, e.g., chloride and the like, or the anhydride thereof. It may be per-formed in the presence of an inert solvent, for example, in a hydrocarbon, such as a lower alkane, e.g., pentane, hexane and the like, or a monocyclic carhocyclic aryl hydrocarbon, e.g., benzene, toluene, xylene and the like, or in a tertiary organic base, such as a liquid pyridine compound, e.g., pyridine, collidine and the like. Acylation may also be achieved in the absence of a solvent, for example, by heating the amidine compound or a salt thereof with the acylating reagent, for example, acetic acid anhydride in a sealed tube.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material ond the remaining step(s) of the process is (are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 A mixture of 18.5 g of 3-(1-N,N-hexamethylene-imino)-propionamidoxime and 5 g. of rhodium on aluminum oxide in 100 ml. of anhydrous ethanol is treated at room temperature with hydrogen under a pressure of about 3 /2 atmospheres while shaking. The calculated amount of hydrogen is absorbed in five hours; the reaction mixture is filtered directly into a cooled solution of hydrogen bromide in ethanol, and the crystalline precipitate is filtered ofr. The desired 3-'(1-N,N-hexamethylene-imino)-propionamide dihydrobromide of the formula is purified by recrystallization from a mixture of ethanol and hexane and melts at 164-466".

The starting material used in the above reaction may be prepared as follows: 50 g. of N,N-hexamethyleneimine is slowly added to 212 g. of acrylonitrile. with stirring. During the addition the reaction mixture warms up; benzyl-trimethyl-ammonium hydroxide (as a 38 percent aqueous solution) is added after the initial reaction subsides, and the mixture is refluxed for about 1% hours. Stirring is continued overnight at room temperature; the excess acrylonitrile is removed under reduced pressure and the residual liquid is fractionated to give 3-(1-N,N- hexamethylene-imino)-propionitrile, B.P. 121123 C./ 14 mm., n =1.4710.

30.4 g. of 3-(1-N,N-hexamethyleue-imino)-propionitrile is added to a solution of about 13.9 g. of hydroxylamine hydrochloride in 300 ml. of anhydrous ethanol.

M.P. l83185 (decomposition).

A solution of sodium ethylate containing 4.6 g. of sodium in 150 ml. of anhydrous ethanol is slowly added to the mixture with stirring. After the addition is completed, the reaction mixture is refluxed for 3 hours and allowed to stand at room temperature for 72 hours. Solid material is filtered from the reaction mixture, and the filtrate concentrated under reduced pressure to give a pale yellow oil of 3-(1-N,N-hexamethylene-imino)-propionamidoxirne. The dihydrochloride of this product'is formed by dissolving the oil in anhydrous ethanol, gassing with dry hydrogen chloride and adding ether. The crystalline 3-(1- N,N-hexamethylene-imino)-propionamidoxime dihydrochloride precipitates and is recrystallized from ethanol, The salt is converted into the free base by dissolving the former in a small amount of water, adding a 40 percent aqueous solution of sodium hydroxide and extracting the organic material with chloroform. The chloroform is evaporated and the residue is recrystallized from xylene to yield the 3-(1- N,N-hexamethylene-imino)-propionamidoxime, M.P. 82.

Other compounds, such as the 2-(1-N,N-hexamethylene-imino)-acetoamid=ine, 3-(1 piperidino)-propionamidine, 3-(1 N,N-heptamethylene-imino)-propionamidine are prepared according to the above procedure or any of the previously-described methods.

Example 2 To a cold 10 percent solution of anhydrous ammonia in anhydrous ethanol is added 14.75 g. of ethyl 3-(1-N,N-

hexamethylene imino) pr-opiothioirnidate dihydrcbromide. The mixture is shaken at room temperature for 48 hours, and is then diluted with hexane. The resulting precipitate is filtered 01f and recrystallized from a mixture of ethanol and hexane to yield 3-(l-N,N-hexamethyleneimino.)-propionamidine dihydrobromide, which is identical with the compound obtained according to the procedure descrbed in Example 1.

The starting material may be prepared as follows: Through a cold mixture of 15.2 g. of 3-(1-N,N-hexamethylene-imino)-propionitrile and 7.0 g. of ethylmercaptan in ml. of chloroform is passed gaseous hydrogen bromide for thirty minutes while stirring occasionally.

The resulting solution is allowed to stand overnight in the cold, the white precipitate is filtered oif and purified by dissolving it in chloroform and precipitating it with hexane. The desired ethyl 3 (1 N,N-hexamethyleneimino)-propiothioimidate dihydrobromide of the formula N-CHzCHz-C\ .2HB

SC H

melts at 152-154".

Example 3 Example 4 A mixture of 11.5 g. of 3-(1-piperidino)-propionamidoxime (prepared from the dihydrochloride as shown in Example 1, M.P. 140-142 after recrystallization from xylene) and 3.38 g. of a rhodium catalyst (rhodium on aluminum oxide, 5 percent) in ml. of anhydrous The solution is concentrated, thev g 7 ethanol is treated with about 3% atmospheres, and the desired 3-(1-piperidino)- propionamidine.dihydrobromide of the formula NH 7 y p NCH1CH .2HBr

is isolated as described in Example 1; it is purified by recrystallization from a mixture of ethanol and hexane, M.P. 169-170. a Example;

A mixture at 19.9 g. of the oily 3-(1-N,N-h$ptan'1 6ihylene-imino)-propionamidoxime (prepared'from the dihydrochloride according to the method shown in Example 7 '1) and g. of the rhodium catalyst in 100 ml. of ethanol 'is treated Withhydrogen as described in Example 1; the desired 3 1-N,N-l1ept amethylene-imino -pr.opionamicline is isolated as the dihydrobromide of the formula j and melts at 176-17 8 after recrystallization from'a mixture of ethanol and diethyl ether.

' E xample. 6 V a A mixture of 13.0 g, of 2-(1-N,N-hexamethylene imino)-acetamidoxime in 200 ml. of, anhydrous ethanol 'and 6.0g. of a rhodium catalyst (6 percent rhodium on .sure of about 3.1 atmospheres while shaking until the hydrogen under a pressure. of

' zene while stirrin g.

' "aluminum oxide) is treated with hydrogen under a pres- I -theoretical amount has been absorbed. The reaction .mixture is directly filtered into a cold saturated solution 'of hydrogen bromide in ethanol, and the resulting 2-(1- N,N-hexamethylene-imino)-acetarhidine dihydrobromide 'of the formula ,isfiltered off and recrystallized from a mixture of hexane and ethanol, and from ethanol, ALP.- l86188; yield:

9.5 gl; 7 V

Example 7.

A mixture of 10.0 g. of 4-(1-N,N-hexamethylene-imino)-butyroamidoxime in ml. of absolute ethanol and 5.0 g. of a rhodium catalyst (5 percent rhodiumbn alurninurn oxide) is treated with hydrogen at a pressure of 3.1 atmospheres while shaking. After the uptake of the theoretical amount of hydrogen, the reaction mixture is directly filtered into a saturated solution of hydrogen bromide in dry ethanol; The resulting precipitate is filtered ofi? and recrystallized from a mixture of ethanol and hexane. to yield 7.0 g..of 4-(1-N,N-hexamethylene-- What is claimed is: V i r A is lower alkylene.

of. N,N-'hexamethylene-imine in ml. of benzene is added 40.0 g. of 4-bromobutyronitrile in 60 of ben Refiuxing is continued for an addi tional five hours the reaction mixture is filteredand the filtrate is concentrated under reduced pressure to yield the 4-( l-'N,N hexamethylene-imino) -butyronitrile, which is purified by distillation and'collected at 129 130/ 15 n1m.; yield: 36.2 g. e a

T0 a solution of 12.66 g. of hydroxylamineghydrochloride in 450ml. of ethanol is added 36.2:g{of the 4-'(1-N,Nhexamethylene-imino)-butyronitrile and'then a solution of 4.22 g. o fsodium in 250 mLofxethanol. The

reaction mixture is refluxed for three hours, and is then allowed to stand overnight and concentrated under re-. .duced pressure. On cooling, the desired*4 (1-N;N hexamethylene-imino) -butyroamidoximesolidifies and is recrystallized from a mixture of hexane and ethanol, M.P.-

in which R is a member selected from the rch .con-- sisting of hydrogenand methyl, n stands for -an integer selected from the group consisting of 5,6, 7 and 8, and A is lower. alkylene.

2. A' pharmacologically in which R is a member selected from the group consisting of hydrogen and methyl, n stands, for 'an integer selected from the group consisting of 5, 6, 7 and 8, and

s. 3-(1-N,N-hexamethylene-imino)-propionamidine.

4. A:pharmacologically acceptable, non-toxic acidaddition salt of 3-(1 N,N-hexamethylene-imino) -propion-;;

amidine, H

5. 3-(1-\l,N-hexamethylene-imino') -propionamidine dihydrobromide. e

"6. 3-(1-N,N-heptamethylene-imino)-propionamidine. V 7. A pharmacologically acceptable acid. addition'salt of 3-(1-N,N-l1eptamethylene-imino) pr opionamidine.

. 8. 3- (1-N,N-heptamethylene-irnino) propionamidine '7 I dihydrobromide.

ReferencesCited by the Exminer UNITED'STATES PATENTS 2,375,611 5/45 Barber et al. 260f293 2,897,195 7/59 Mull 260293 2,928,829 3/60 Mull 260293 2,947,782 8/60 'De Bonneville et a1. 26()293 IRVING MARC S, Primary Examiner.

NICHOLAS, s. RIZZO, WALTER A. 'MODANCE,

Examiners.

alkano-amidineof the 7' acceptable, non-toxic acid ad- 9 'dition salt of an N,N-alkylene-irnino-lower alkano -amia dine of the formula r 

1. AN N,N-ALKYLENE-IMINO-LOWER ALKANO-AMIDINE OF THE FORMULA 